CN1029680C - Technology for phenyl fluorenol (an antimalarial) synthesis - Google Patents
Technology for phenyl fluorenol (an antimalarial) synthesis Download PDFInfo
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- CN1029680C CN1029680C CN 88107666 CN88107666A CN1029680C CN 1029680 C CN1029680 C CN 1029680C CN 88107666 CN88107666 CN 88107666 CN 88107666 A CN88107666 A CN 88107666A CN 1029680 C CN1029680 C CN 1029680C
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Abstract
The present invention relates to a novel synthetic technology of new medicine, namely benflumetol alpha-(n-butylaminomethyl)-2.7-dichloro-9-p-chlorbenzylidene-4-fluorenylmethanol, for treating chloroquine-resistant pernicious malaria. The present invention has the synthetic route that (1) benflumetol is prepared from industrial fluorene (1) by five reaction steps of chlorination reaction, Friedel-Crafts reaction, potassium borohydride reaction, di-n-butylamine reaction and condensation with p-chlorobenzaldehyde. The synthetic route is shorter than that of the existing synthetic route (needing 10 to 12-step reaction). The total yield is 15%+/-66% higher than that (9%+/-66%) of the existing technical scheme. The synthesis technology has low consumption of raw materials, eliminates the two reaction steps of dichloro-butylamine and heavy methyl chloride prepared in the existing synthetic route (both of N-nitroso-N-dimethylurea and the heavy methyl chloride as raw materials for preparing heavy gas methane are strongly carcinogenic toxic substances and are flammable and explosive), reduces environmental pollution and ensures safety production. The benflumetol prepared by the synthetic technology of the present invention has clinical effective rate of 100% on chloroquine-resistant pernicious malaria, has treatment rate more than 96% and has treatment effect of 3.2 times higher than that of chloroquine (treatment rate is 30%).
Description
The present invention relates to the new synthesis process of the anti-chloroquine pernicious malaria of a kind of treatment new drug phenyl fluorenol (α-(two n-butyl amine methyl)-2,7-two chloro-9-are to chlorobenzene methylene radical-4-Lumefantrine) compound.Belong to the medical and health manufacturing process.
Up to extremely at present, in the existing similar technology, still there is not the report that reacts new synthetic process with the present invention same or analogous five steps both at home and abroad, have only phenyl fluorenol intermediate IV, V synthetic document record (1,2,3).As preparation phenyl fluorenol intermediate IV such as Atkinson in 1974 was from anthranilic acid (I), through compound 2,3,4,5,6,7,8, needed the reaction of 8 steps just can finish altogether.Its reaction equation is as follows:
According to above-mentioned reaction equation, in the synthesis flow of existing phenyl fluorenol intermediate (IV), still needing increases the heavy ammonia methane of preparation (CH
2N
2) and dichloramine-T (
) two synthesis steps.Therefore, finish the production of phenyl fluorenol, need the reaction scheme of 10～12 steps altogether.
The technical characterictic of phenyl fluorenol new synthetic process provided by the present invention is:
1. technical scheme is new, technical process short.5 steps reaction of the present invention is that with the fundamental difference of prior art innovation and technical process on the technical solution of the present invention are short, from selecting industrial fluorenes (I) for use, produce 2 through chlorination reaction, 7-dichloro fluorenes (II), II and chloroacetyl chloride carry out the Fu Shi reaction and produce 2,7-dichloro fluorenes-4-chloroethene ketone (III), III and POTASSIUM BOROHYDRIDE reaction produce 2,7-dichloro fluorenes-4-oxyethane (IV), α-(two n-butyl amine methyl)-2 produced in IV and Di-n-Butyl Amine reaction, 7-two chloro-4-Lumefantrines (V), V and 4-chloro-benzaldehyde condensation obtain the end product phenyl fluorenol.Its reaction scheme is as follows:
According to reaction equation, 5 step of phenyl fluorenol new synthetic process provided by the invention, the synthetic of intermediate (IV) only needs 3 to go on foot reaction (prior art needs the reaction of 8 steps).Obtain the end product phenyl fluorenol, be no more than 5 reactions steps (prior art needs 10～12 reactions steps) altogether, thereby shortened technical process, save starting material and time.
According to reaction equation, because the diazomethane and the dichloramine-T two-step reaction that cause public hazards have easily been discarded in the innovation on the 5 step reaction technology schemes of the present invention fully.The prior art scheme, synthetic phenyl fluorenol intermediate (IV) needs the preparation diazomethane, in order to prepare diazomethane, must preparation N-nitroso-group-N-methyl urea.This compound and diazomethane all have bigger toxicity, belong to strong carcinogen, and inflammable and explosive, are absolutely unsafe.Adopt synthesis technique of the present invention to produce phenyl fluorenol, can make the corresponding improvement of deleterious production environment condition, reduced the environmental pollution that causes because of the three wastes.
2. overall yield is higher than the prior art scheme.Adopting the synthetic phenyl fluorenol of prior art, its overall yield is 9% ±, synthesis technique provided by the invention, its overall yield is 15% ±, be higher than prior art 66%.
3. the phenyl fluorenol of producing with synthesis technique of the present invention, the clinical efficacy height.Economize 576 routine anti-chloroquine pernicious malaria patient being used for Yunnan, Hainan etc., its clinical effective rate 100%, curative ratio are more than 96%, are 3.2 times of chloroquine (curative ratio 30%).
The technology implementation example.
According to 5 step synthetic routes, the embodiment that provides new antimalarial agent phenyl fluorenol new synthetic process is as follows.
Implement 1:2, synthetic (chlorination reaction) of 7-dichloro fluorenes (II).
With industrial Glacial acetic acid 1200ml, water 40ml, fluorenes 120g and iron trichloride 7.2g, the adding capacity is in the there-necked flask of 2 liters successively, weighs mechanical stirring.When in ink is bathed, heating reflux condensing tube is installed.When treating that temperature reaches 35 ℃, feed chlorine from grass tube, temperature remains on 37～41 ℃, stops ventilation when weightening finish 100～110g.Continue down to stir 2 hours at 40 ℃.More than the temperature adjustment to 90 ℃, stir a moment then, pour in the beaker, to be cooled during to room temperature, a large amount of plate crystals of separating out are filtered, wash, refluxed 1 hour naturally cooling, filter collection product 61～73g with the 1500ml industrial ethyl alcohol.Fusing point is 120～127 ℃ (molten apart from 3～4 ℃).2.7-the productive rate of dichloro fluorenes is 36.1～43.0%.
Embodiment 2:2, synthetic (the Fu Shi reaction of chloroacetyl chloride) of 7-dichloro fluorenes-4-chloroethene ketone (III).
With exsiccant 1,2-ethylene dichloride 700ml places capacity 1 liter there-necked flask, adds chloroacetyl chloride 24g(0.184M), aluminum trichloride (anhydrous) 42g(0.312M).Under agitation when 0～5 ℃ of Nei Wenda, gradation adds 2,7-dichloro fluorenes 40g(0.17M), added in about 30 minutes, keep 0～5 ℃, reacted 2～3 hours.Allow it heat up naturally, reacted again 2～3 hours.Reactant is slowly poured in the 1 liter frozen water that contains the 250ml concentrated hydrochloric acid then, be stirred well to and tell organic layer, water layer is with 1, and 2-ethylene dichloride washing secondary merges washing lotion and organic layer, washes with water to not showing acid substantially.Steam solvent, add about 2 liter industrial alcohols, boil to complete molten after-filtration, cooling filtrate is separated out solid.Get product 38～44g, 118～126 ℃ of melting ranges (molten) apart from 3～5 ℃.Concentrated mother liquor can be separated out the about 5g of portioned product again, and fusing point is more than 116 ℃, altogether product 43～49g.Productive rate 81.5～92.7%.
Embodiment 3:2, synthetic (the potassium borohydride reduction reaction) of 7-dichloro fluorenes-4-oxyethane (IV)
In the 500ml there-necked flask, place 2,7-dichloro fluorenes-4-chloroethene ketone 20g, industrial POTASSIUM BOROHYDRIDE 6g and dehydrated alcohol 300ml.Temperature is 40～45 ℃ in the control, stirring reaction 9 hours.Placement is spent the night, and collects white solid, uses bubble, filters, and is washed with water to filtrate and is neutral substantially.Below 60 ℃, dry to constant weight, get white solid, 126～36 ℃ of fusing points (molten) apart from 4 ℃.The ethanol mother liquor is concentrated, and room temperature is placed cooling, separates out a small amount of faint yellow solid again, fusing point 120～30 ℃ (molten) apart from 4 ℃ altogether product 12.5～14.2g, productive rate 70～80%.
Embodiment 4: α-(two n-butyl amine methyl)-2, synthetic (two positive fourths are by the reaction) of 7-two chloro-4-Lumefantrines (V).
In the 200ml round-bottomed flask, place 2,7-dichloro fluorenes-4-oxyethane 20g, Di-n-Butyl Amine 14g and dehydrated alcohol 120ml, reflux 14 hours, filtered while hot after filtrate is cold, is separated out the yellowish white solid, filter, oven dry below 40 ℃ gets 23.4～24.0g, 74～9 ℃ of fusing points (molten apart from 2 ℃), α-(two n-butyl amine methyl) 2, the productive rate of 7-two chloro-4-Lumefantrines is 80～85%.
Embodiment 5: α-(two n-butyl amine methyl) 2,7-two chloro-9-are to chlorobenzene methylene radical-4-Lumefantrine (with the 4-chloro-benzaldehyde condensation, generating the end product phenyl fluorenol).
On the 500ml there-necked flask, install agitator, Calcium Chloride Powder Anhydrous drying tube and thermometer, add dehydrated alcohol 300ml then, granular sodium hydroxide 3.5g, stirring and dissolving under the room temperature, add α-(two n-butyl amine methyl)-2,7-two chloro-4-Lumefantrine 10g are at 25 ℃ of left and right sides stirring reactions, approximately through 30 minutes, faint yellow solid is separated out in the dissolving of overwhelming majority solid later on gradually.React after 24 hours and placed 1-2 days, filter, wash with water and leach thing to nothing alkalescence, oven dry below 60 ℃, the gained coarse products is faint yellow solid 9～10.5g, 122～127 ℃ of fusing points (molten apart from 2～3 ℃).Raw product dehydrated alcohol recrystallization gets the faint yellow crystallization of phenyl fluorenol 7.6～8.9g, 125～131 ℃ of fusing points (molten) apart from 2～3 ℃, and productive rate is 60～70%.
Reference
1.AD 752624
2.Atkinson ER，efal：J.Med，Chem.17：
1009，1974
3. Deng Rong celestial being etc.: Acta Pharmaceutica Sinica 16 920,1981
Claims (1)
- A kind of new synthetic process of new antimalarial agent phenyl fluorenol, produce 2 by industrial fluorenes (I), 7-dichloro fluorenes (II) produces 2 by (II), 7-dichloro fluorenes-4-chloroethene ketone (III), produce intermediate 2 by (III), 7-dichloro fluorenes-4-oxyethane (IV) is produced α-(two n-butyl amine methyl)-2 by (IV), 7-two chloro-4-Lumefantrines (V), make end product α-(two n-butyl amine bases)-2 by (V), 7-two chloro-9-is characterized in that chlorobenzene methylene radical-4-Lumefantrine (being phenyl fluorenol):By industrial fluorenes (I) through oxidizing reaction system 2,7-dichloro fluorenes (II):2. by 2,7-dichloro fluorenes (II) produces 2,7-dichloro fluorenes-4-chloroethene ketone (III) through chloroacetyl chloride Fu Shi reaction3. by 2,7-dichloro fluorenes-4-chloroethene ketone (III) is produced intermediate 2 through potassium borohydride reduction, 7-dichloro fluorenes-4-oxyethane (IV)
4. by 2,7-dichloro fluorenes-4-oxyethane (IV) is produced α-(two n-butyl amine methyl)-2,7-two chloro-4-Lumefantrines (V) through the Di-n-Butyl Amine reaction
5. by α-(two n-butyl amine methyl)-2,7-two chloro-4-Lumefantrines (V) are produced α-(two n-butyl amine methyl)-2 with the condensation of parachlorotoluene aldehyde, and 7-two chloro-9-are to chlorobenzene methylene radical-4-Lumefantrine (being phenyl fluorenol)
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|---|---|---|---|
| CN 88107666 CN1029680C (en) | 1988-11-10 | 1988-11-10 | Technology for phenyl fluorenol (an antimalarial) synthesis |
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| CN 88107666 CN1029680C (en) | 1988-11-10 | 1988-11-10 | Technology for phenyl fluorenol (an antimalarial) synthesis |
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| CN1042535A CN1042535A (en) | 1990-05-30 |
| CN1029680C true CN1029680C (en) | 1995-09-06 |
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| CN 88107666 Expired - Fee Related CN1029680C (en) | 1988-11-10 | 1988-11-10 | Technology for phenyl fluorenol (an antimalarial) synthesis |
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Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058717A (en) * | 1990-08-08 | 1992-02-19 | 中国人民解放军军事医学科学院微生物流行病研究所 | New antimalarial agent-Coartem and preparation method thereof |
| CO5040050A1 (en) * | 1998-06-25 | 2001-05-29 | Novartis Ag | COMPOUNDS OF 2-AMINO-1- (9-ARYLMETYLIDINE-2,7-DICLORO-9H- FLUOREN-4-ILO) -N-SUBSTITUTED TANOLS, PROCEDURES FOR THE OBTAINING AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| CN102344423A (en) * | 2011-07-27 | 2012-02-08 | 安徽省郎溪县联科实业有限公司 | Method for refining 2,7-dichlorofluorenyl-4-ethylene oxide |
| GB2515909B (en) * | 2012-01-31 | 2020-07-15 | Cambridge Display Tech Ltd | Composition comprising a fluorescent light-emitting material and triplet-accepting polymer and use thereof |
| CN103193588A (en) * | 2013-04-12 | 2013-07-10 | 彭学东 | New technology for synthesizing 2,7-halogenated fluorene derivative with industrial fluorene as raw material |
| CN103319356A (en) * | 2013-06-17 | 2013-09-25 | 张家港威胜生物医药有限公司 | One-step green synthesis process of antimalarial raw material benflumetol |
| CN103353487A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | High performance liquid chromatography method for determination of lumefantrine content |
| CN103408509A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Anti-malaria medical raw material benflumetol intermediate 2,7-dichlorofluorene-4-ethylene oxide synthesis process |
| CN105001044A (en) * | 2015-06-30 | 2015-10-28 | 杭州巴洛特生物科技有限公司 | Synthesis method of 2,7-dichlorofluorene |
| CN107501316B (en) * | 2016-06-14 | 2021-05-18 | 安徽贝克联合制药有限公司 | Phelumefluorenol isomer and preparation method thereof |
| JP7377717B2 (en) | 2017-04-24 | 2023-11-10 | ノバルティス アーゲー | 2-Amino-L-(2-(4-fluorophenyl)-3-(4-fluorophenylamino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-A]pyrazine-7(8H )-il) ethanone and their combination therapeutic regimens |
| CN111039804A (en) * | 2019-12-31 | 2020-04-21 | 日照巴洛特药业有限公司 | Benflumetol preparation method and matching system thereof |
| CN111686096B (en) * | 2020-07-24 | 2021-05-14 | 中国人民解放军军事科学院军事医学研究院 | Application of lumefantrine and derivatives thereof in preparation of drugs for treating coronavirus infection |
| CN114436866A (en) * | 2022-01-19 | 2022-05-06 | 舞阳威森生物医药有限公司 | Refining process of benflumetol crude product |
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